Psoriatic skin contains more nerve fibers and increased levels of sensory nerve-derived calcitonin gene related peptide (CGRP) and substance P (SP). Interestingly, several case reports have demonstrated psoriatic plaque resolution following accidental skin denervation, and subsequent loss of nerve-derived factors. These results imply a role for the nervous system in maintaining and exacerbating the psoriasis phenotype; however the role and contribution of nerves to the cellular and molecular mechanisms mediating cutaneous inflammation and hyperplasia remains poorly defined. Recent work from our group has identified increases in cutaneous nerve fibers and nerve-derived SP and CGRP in the KC-Tie2 murine model of psoriasiform dermatitis providing an experimental paradigm to explore neural contributions to psoriasis pathogenesis. Following surgical elimination of all nerve fibers entering dorsal skin of KC-Tie2 mice, a 40% decrease in CD11c+ dendritic cells (DCs) was observed beginning 1 day (d) following surgery, followed by a 30% improvement in acanthosis by 7d and a 30% decrease in CD4+ T cells by 10d. These outcomes were SP and CGRP dependent; as reconstitution of SP and CGRP in denervated KC-Tie2 skin prevented phenotype improvement and inhibition of SP and CGRP in innervated KC-Tie2 skin recapitulated the findings elicited by experimental denervation in a neuropeptide specific manner. Similar levels of improvement were observed following one intradermal injection of Botulinum toxin A, a well characterized inhibitor of nerve-derived CGRP/SP. Together these results identify nerve-derived SP and CGRP as critical mediators of psoriasisform skin inflammation, and offer a potential mechanism explaining case and anecdotal reports of nerve-dependent clearing, and provide a unique and innovative opportunity for identifying new therapeutic avenues. To identify the cellular targets affected by nerve-derived SP and CGRP as well as the potential mechanism(s) used to direct KCs, DCs and T cell response that translates to sustaining inflammation and acanthosis in psoriasis, we propose to: (1) stimulate KCs, DCs or T cells in vitro with SP or CGRP and quantitate changes in cell proliferation and differentiation, leukocyte migration and the production of DC- and T cell-derived cytokines and KC-derived leukocyte chemoattractants, in the presence/absence of pharmacological inhibitors of SP and CGRP; and (2) alter SP and CGRP direct effects on KCs and skin- derived immune cells using a combination of transgenic and skin transplant strategies designed to compartmentalize skin specific immunomodulatory responses utilizing T cell-deficient mice and diphtheria toxin receptor inducible DC-depleted mice coupled to SP- and CGRP-receptor deficient mice. The information gained from our studies will identify the cellular targets affecte by nerve-derived SP and CGRP as well as the potential mechanism(s) used to direct KCs, DCs and T cell response that translates to sustaining inflammation and acanthosis in psoriasis.